The overall goal of our Research Program is to identify the elements that initiate, intensify and modulate the inflammatory response in the asthmatic airway. Our Program is comprised of three highly synergistic Projects interconnected through the unifying hypothesis that asthma results from prolonged and active airway inflammation with failed attempts at resolution and repair leading to tissue destruction and remodeling. Projects are specifically aimed at defining mechanisms behind the well-established histopathology observed in asthmatic airways: injury and denudation of the airway epithelium (project 1), increased and aberrant deposition of extracellular matrix components (project 2), and airway injury through oxidative processes of eosinophils and neutrophils (project 3). The Research Program is comprehensive in that Projects will study the pro-inflammatory and inter-related roles of extracellular and cellular components, including leukocytes and resident smooth muscle and airway epithelial cells. Project 1 investigates how epithelial cells are active participants in inflammation through excessive nitric oxide synthesis, and downstream consequences of protein oxidation via exposure to NO-derived oxidants. Project 2 expands upon the pro-inflammatory role of resident cells, as it identifies how smooth muscle and epithelial cells participate in inflammation through synthesis of an extracellular hyaluronan matrix that is critical for recruitment/migration, proliferation, and activation of CD44 (+) leukocytes, e.g., monocytes/macrophages, mast cells, and eosinophils. Project 3 studies the oxidative processes mediated by key effector cells in asthma, eosinophils and neutrophils, and investigates whether or not oxidative products are useful as monitors of inflammation. Three scientific Cores (Clinical, Tissue Processing and Cell Culture, and Animal Model) and an Administrative Core significantly strengthen each Project and the overall Program by providing expertise, service, easy access to well-defined clinical samples and primary human cells in culture, and a murine allergen-induced airway inflammation asthma model, to all projects. Collectively the Projects, supported by Cores, allow our Program to comprehensively address fundamental mechanisms involved in the inflammatory processes leading to asthma clinical pathology, including acute exacerbations, chronic airway inflammation, and airway remodeling.